There is a variety of evidence that pathogens may be able to suppress the body's defenses, particularly immune defenses, against infection by up- or down-regulating specific cytokines that play a role in the immune response. For example, Yersinia infection suppresses TNF-alpha release by macrophages (Boland and Cornelis 1998; Cornelis and Denecker 2001); the adenovirus E3 protein is an antagonist of TNF cytolysis (Tufariello, Cho et al. 1994; Tufariello, Cho et al. 1994); and Mycobacterium tuberculosis inhibits LPS-induced IL-12 production by human dendritic cells (Nigou, Zelle-Rieser et al. 2001).
Multiple pathogens, particularly intracellular pathogens, appear to up-regulate IL-10 production, as a strategy for inhibiting removal of the pathogen by the immune system. (Moore, de Waal Malefyt et al. 2001). Stockl et al. showed that human rhinoviruses (HRV) suppress the accessory function of monocytes by inducing IL-10 (Stockl, Vetr et al. 1999). Respiratory syncytial virus (RSV) causes an excessive IL-10 response leading to downregulation of antiviral defense mechanisms and reduced elimination of respiratory pathogens (Miyada and Wallace 1987; Guerrero-Plata, Casola et al. 2006). Fleming et al show that an IL-10 homologue is encoded by the poxvirus orf virus (Fleming, McCaughan et al. 1997). Viral homologues of IL-10 have also been found in Epstein-Barr virus (Suzuki, Tahara et al. 1995) and equine herpes virus. Epstein-Barr virus (EBV) also induces IL-10 expression in Burkitt's lymphoma cells (Vockerodt, Haier et al. 2001). Specifically, EBV encodes a human IL-10 homolog as well as the EBV latent protein-1 that induces IL-10 and both of these EBV factors are thought to facilitate viral survival and pathogenesis through IL-10's immune suppressive activity.
The human immunodeficiency virus (HIV) envelope gene products have been shown to induce IL-10 expression in monocytes (Koutsonikolis, Haraguchi et al. 1997; Taoufik, Lantz et al. 1997; Barcova, Kacani et al. 1998) and to induce anergy in human peripheral blood lymphocytes (Schols and De Clercq 1996). These findings indicate that IL-10 plays an important role in the inhibitory effect of gp120 on PBMC proliferation and could contribute to the depressed immune responses associated with human immunodeficiency virus infection and thus have important implications for immunotherapeutic strategies to slow down disease progression in AIDS. Furthermore, a negative correlation was observed between IL-10 serum levels and CD4+ T-cell counts in HAART naïve, HIV-infected patients and that the increase in IL-10 serum levels in HIV-1-infected patients is associated with the progression of immune deficiency (Orsilles, Pieri et al. 2006).
IL-10 has been shown to play a critical role in a murine model of M. bovis Bacillus Calmifte-Guerin (BCG) infection since IL-10 over-expression enhanced bacilli growth and an IL-10 knock-out mouse showed increased anti-mycobacterial immunity, lowered BCG load and increased levels of pro-inflamatory cytokines (Murray and Young 1999). This suggests that IL-10 is an inhibitor of early mycobacterial clearance and negatively regulates numerous macrophage functions as well as playing a role in down-regulating the general inflammatory response (Jacobs, Brown et al. 2000). Clinical data also lend support for IL-10 in tuberculosis pathogenesis, (Gong, Zhang et al. 1996) lending further support that L-10 mediates the anergy seen in patients with active tuberculosis (Boussiotis, Tsai et al. 2000). Furthermore, a polymorphic allele of the IL-10 gene plays an important role in determining susceptibility to TB (Oral, Budak et al. 2006; Oh, Yang et al. 2007).
IL-10 may also be involved in susceptibility to several other human pathogens including Listeria monocytogenes, lymphocytic choriomeningitis virus (LCMV) and Hepatitis C virus (HCV) infections. Biswas, et al demonstrated that IL-10 inhibits CD8 T cell responses by restricting T cell expansion during primary and memory responses to L. monocytogenes infection (Biswas, Pedicord et al. 2007). Ejrnaes, et al show that IL-10 production is drastically increased in mice persistently infected with LCMV and that in vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid resolution of the persistent infection (Ejrnaes, Filippi et al. 2006). The HCV nonstructural protein 4 (NS4) induces peripheral blood mononuclear cells (PBMC) to secrete IL-10 and inhibits IL-12 production by PBMC in response to LPS and IFN-gamma (Brady, MacDonald et al. 2003). Increased concentrations of IL-10 in chronic HCV-infected, interferon alpha and ribavirin nonresponder patients compared to baseline IL-10 levels in those with a complete response and suggest that IL-10 may inhibit Th1 cells and the host immune response against HCV (Marin-Serrano, Rodriguez-Ramos et al. 2006). These results suggest that HCV subverts cellular immunity by inducing IL-10 and inhibiting IL-12 production by monocytes, which in turn inhibits the activation of DC that drive the differentiation of Th1 cells. Furthermore, therapeutic administration of an antibody that blocks the IL-10 receptor restored T-cell function and eliminated a persistent LCMV infection (Brooks, Trifilo et al. 2006). Along these same lines, a monoclonal antibody-induced blockade of IL-10R increases the CD4+ T-cell responses to HCV antigens and suggests that IL-10R blockade with a human monoclonal antibody has the potential to alter the host immune response to HCV (Rigopoulou, Abbott et al. 2005).
IL-10 also is known to play a role in the development of cancer (Dercamp, Chemin et al. 2005). Elevated levels of IL-10 mRNA have been observed in immune-responsive versus non-responsive metastatic melanoma lesions (Mocellin, Ohnmacht et al. 2001). Dercamp, et al show that IL-10 and regulatory T cells (Treg) act together to impair antitumor CD8+ T cell effector differentiation and induce tumor-induced antigen-specific anergy in CD8+ T cells (Dercamp, Chemin et al. 2005). Furthermore, treatment with a combination of anti-IL-10R monoclonal antibody and toll-like receptor 9 ligands has been shown to be an effective anti-tumor therapeutic regimen (Vicari, Chiodoni et al. 2002).
It would thus be desirable to provide a therapeutic compound that is effective in suppressing functional IL-10, or IL-10 signal transduction as a treatment modality during infection, in the treatment of cancers in which IL-10 overproduction may subvert the body's ability to mount an immunological defense against the cancer, and as an adjunct for vaccines, to enhance immune responsiveness to the vaccine.